JP2007530497A - Nanocomposites of platinum compounds - Google Patents

Abstract

  Solid lipid nanoparticles of platinum compounds, in particular antitumor platinum complexes, are disclosed. The nanoparticles of the present invention are prepared by mixing a) a molten lipid, a surfactant and optionally a co-surfactant, and an aqueous platinum compound; b) a surfactant and optionally a co-surfactant. Prepare the solution by mixing the surfactant in water, preferably at the same melting temperature as the lipid used in a) to complete solution and adding the cosurfactant; c) a) The microemulsion obtained in step b) is dispersed in the solution obtained in b) to obtain multiple microemulsion c); Disperse to obtain solid lipid microspheres; e) The lipid microspheres obtained in d) are washed with an aqueous medium through ultrafiltration and optionally frozen in the presence of swelling agents and cryoprotectants. Obtainable by a process comprising 燥.

Description

  The present invention relates to treatment-related platinum compound solid lipid nanoparticles.

BACKGROUND OF THE INVENTION Solid lipid nanoparticles or microparticles (SLN or SLM) or nanospheres are lipid particles, typically in the range of hundreds to nanometers, with an average diameter of less than 1 micron, which are controlled It has been thoroughly studied as a carrier for drug delivery. SLN can be made from solid lipids by several methods including, for example, via high pressure homogenization (EP605497) and microemulsions (US 5,250,236).

  A review of SLN production and pharmaceutical applications is reported, for example, in Eur. J. Pharmaceutics and Biopharmaceutics, 50 (2000), 161-177 and Pharm. Technol. Eur. 13 (2001) 32-42.

  A pharmaceutical composition in the form of an SLM suitable for parenteral administration of drugs is disclosed in particular in EP 988031. The formulation is characterized by certain compounds such as fatty acids, PEG-stearate, dipalmitoyl phosphatidylethanolamine-PEG and the like, which avoid phagocytosis and stabilize the microparticles.

  Microparticles that are particularly suitable for drug delivery across the mucosal tissue and blood brain barrier are disclosed in WO 99/27918 and US 6,419,949. Several medications have been specifically described, including different types of antibiotics, hormones and antitumor agents.

Platinum compounds are one of the most effective anticancer drugs used to treat solid tumors. Following intravenous administration, platinum species tend to bind irreversibly (covalently) to plasma proteins with time-dependent kinetics, with more than 90% of the drug binding within hours of administration. In addition, in some new platinum complexes, some of the drugs that are released in plasma water and reversibly bind to plasma proteins undergo progressive and rapid degradation to produce inactive deplatinized species. These species appear to arise due to chemical instability of platinum compounds in plasma, presumably due to interactions with nucleophilic thiol-containing endogenous molecules (eg cysteine residues, glutathione). The high degree of plasma protein binding in humans probably favors such interactions. Both high irreversible binding to plasma proteins and rapid degradation in human plasma appear to inhibit the efficacy of platinum compounds in clinical trials.
Description of the invention

  Platinum compounds with antitumor activity can advantageously be formulated into SLN or SLM, surprisingly improving its therapeutic index.

  According to the invention, preferred platinum compounds include platinum complexes in which the platinum metal atom is chelated by a suitable ligand, in particular an anionic ligand and an amino group-containing ligand.

  Preferred compounds are described in US 6,022,892, US 6,060,616, US 5,744,497, US 6,011,166, and US 6,596,889.

Particularly preferred compounds are:
Formula I: described in Example 6 of US 5,744,497:

Trans- {bis [trans (diamine) (chloro) platinum (II) (μ-1,6-hexanediamine)]} diamine platinum tetranitrate,
US Pat. No. 6,022,892, Example 17, page 15, line 15-31, formula II:

Bis {trans (diamine) (chloro) platinum (II)} μ- (1,16-diamino-7,10-diazahexadecane-N ¹ , N ¹⁶ ) dinitrate. 2HNO ₃ ,
US Pat. No. 6,022,892, Example 17, page 15, lines 32-38, formula III

Bis {trans (diamine) (chloro) platinum (II)} μ- (1,16-diamino-6,11-diazahexadecane-N ¹ , N ¹⁶ ) dinitrate. 2HNO ₃ ,
Formula IV as described in Example 2 of US 6,596,889:

Bis {trans (diamine) (chloro) platinum (II)}-μ- (1,12-diamino-4,9-diazadodecane-N ¹ , N ¹² ) dinitrate. 2HNO ₃ ,
Formula V: described in Example 1 of US 6,596,889:

Bis {trans (diamine) (chloro) platinum (II)}-μ- (1,8-diamino-4-azaoctane-N ¹ , N ⁸ ) dinitrate. HNO ₃ .

  Formulations of solid lipid nanoparticles (SLN) of platinum compounds are disclosed in the above patent documents, using solid lipids, surfactants, and co-surfactants as excipients, incorporated herein by reference. It can be obtained using any of the methods.

  Platinum compound nanoparticles are obtained from warm microemulsions using the described technique (US 5,250,236). SLN is placed with a hydrophilic or hydrophobic platinum compound that can be dissolved in the internal phase of the microemulsion.

More specifically, the platinum complex nanoparticles of the present invention comprise:
a) preparing a first microemulsion by mixing molten lipid, surfactant and optionally a co-surfactant, and an aqueous platinum compound;
b) mixing the surfactant and optionally the co-surfactant in water, preferably heating to the complete solution at the same melting temperature as the lipid used in a) and adding the co-surfactant, Preparing a solution;
c) The microemulsion obtained in a) is dispersed in the solution obtained in b) to obtain a multiple microemulsion c);
d) The microemulsion obtained in c) is dispersed in an aqueous medium at a temperature in the range of 0.5-4 ° C. to obtain solid lipid microspheres;
e) The lipid microspheres obtained in d) are washed with an aqueous medium through ultrafiltration and optionally lyophilized in the presence of a swelling agent and a cryoprotectant;
Can be obtained by a method comprising:

  Conventional swellable agents such as dextran and the like may be advantageously used.

  Lipid components used according to the present invention include, for example, triglycerides such as trilaurin, tripalmitin and tristearin, fatty acids such as lauric acid, myristic acid, palmitic acid and stearic acid, myristyl alcohol, cetyl alcohol and stearyl alcohol. Selected from the group comprising various alcohols. Surfactants include sodium cholate, sodium deoxycholate, sodium glycolate, sodium taurocholate, sodium taurodeoxycholate, sodium bis (2-ethylhexyl) sulfosuccinate, lecithin and phospholipid, polyoxyethylene sorbitan fatty acid ester ( For example, from the group comprising Tween 20, Tween 40, Tween 80), sorbitan ester (Span 20, Span 40, Span 60, Span 80), ceramide, singomyelin, galactocerebroside, polyoxypropylene-polyoxyethylene glycol nonionic block copolymer or sucrose fatty acid ester Selected. The co-surfactant is selected from the group comprising low molecular weight alcohols or glycols such as isopropanol, butanol, hexanol, hexanediol, propylene glycol, low molecular weight fatty acids such as butyric acid and hexanoic acid, esters of phosphoric acid and benzyl alcohol.

  Stearic acid is preferred as the lipid substance.

  Preferred surfactants include soy phosphatidylcholine, sodium taurocholate and mixtures thereof.

A preferred co-surfactant is isopropanol. In the production of the microspheres according to the present invention, various substances are used in the following proportions: 4-25% by weight of the total, preferably 4-12% by weight of lipid components that can contain the drug;
Between 40 and 70% by weight of total, preferably between 55 and 65% by weight of water;
Between 8 and 30% by weight of total surfactant, preferably between 12 and 22% by weight;
Cosurfactant between 0 and 15% by weight of total, preferably between 6 and 12%.

  The volume of water for dispersing the warm microemulsion is 5 to 50 times the volume of water, preferably 5 to 20 times the volume of the microemulsion.

  The platinum compound-SLN is spherical in shape with an average diameter of 70-200 nm and is suitable for intravenous and oral administration.

  Platinum compound-SLN is absorbed through the lymph when administered by the oral route. When administered intravenously, SLN can significantly alter the pharmacokinetics of platinum compounds observed after administration of solution formulations. SLN can also enter tumor cells within minutes and can overcome physiological barriers as described in US 6,238,694, US 6,419,949.

  Nanoparticles can be made more elaborately to obtain stealth SLN, and in-network system recognition can be avoided, as described in US 6,419,949.

The use of platinum compound-SLN in the anti-tumor treatment according to the present invention brings the following advantages:
1. Improved oral bioavailability of poorly absorbed platinum compounds or compounds that are unstable in the intestinal lumen;
2. Alleviation of undesired interactions between platinum compounds and gastric / intestinal mucosa after oral administration, thus minimizing local toxicity;
3. Maximization of oral bioavailability by absorption of nanoparticles through the lymphatic system without the first pass effect of the liver;
4). The possibility of administering poorly water-soluble platinum compounds by the parenteral route;
5). Reduced platinum compound-protein binding and increased rate and extent of drug distribution;
6). Protection of platinum compounds from endogenous molecules in the blood that can degrade / inactivate the compounds before reaching the tumor object;
7). Altering the pharmacokinetic profile of an intravenously administered platinum compound by slowing down the drug release from the formulation, thus reducing the peak concentration and increasing the residence time in the systemic circulation. Increasing it;
8). Improved therapeutic index to tumor cells (increased permeability and retention effect) and sustained release of platinum compounds into cells with better anticancer efficacy;
9. Alter drug distribution patterns, including through the blood-brain barrier.

  The platinum compound-SLN of the present invention can be administered to patients suffering from cancers that are normally responsive to platinum compounds, and is preferably formulated in pharmaceutical formulations for oral and intravenous administration. Guidelines for suitable dosing schedules can be found in the above US patents disclosing platinum compounds.

Example Example 1
Bis {trans (diamine) (chloro) platinum (II)} .mu. (1,16-diamino-7,10-diaza-hexadecane -N ^1, N ¹⁶⁾ dinitrate. 2HNO ₃ SLN
Bis of formula II {trans (diamine) (chloro) platinum (II)} .mu. (1,16-diamino-7,10-diaza-hexadecane -N ^1, N ¹⁶⁾ dinitrate. 2HNO ₃ (described in US Pat. No. 6,022,892, Example 17, page 15, lines 25-31) is a potent bisplatinum complex that provides significant antitumor activity in various tumor cell lines. Nanoparticles of this compound were prepared by using an aqueous solution of lecithin, stearic acid, taurocholate, propionic acid, and bisplatinum compound (0.01M NaCl, 0.01M HCl) as described in the above (US 5,250,236). Manufactured by. The warm microemulsion was dispersed in cold water (1-4 ° C.). The nanoparticle dispersion was repeatedly washed with distilled water by ultrafiltration (100,000 Da cut-off).

  HPLC and ICP analysis of the resulting bisplatinum complex-SLN showed that over 90% of the input bisplatinum complex was incorporated into the nanoparticles. The SLN average diameter was 120 nm as measured with a Malvern Zetasizer 3000HS.

  Platinum compounds are stable in human plasma and do not interact with plasma proteins when incorporated into solid lipid nanoparticles. Bisplatinum compound-SLN is well tolerated when administered to CD1 mice and exhibits an improved therapeutic index when compared to an aqueous solution of the same compound.

Example 2
0.4 g of stearic acid was melted at about 71 ° C. and 0.32 g of soybean phosphatidylcholine was added to obtain a hot clear solution. Then 260 μl of propionic acid and 200 μl of compound of formula II (9 mg / ml) in 0.01 N HCl aqueous solution were added to give a clear microemulsion (Micro 1).
Separately, a solution of soy phosphatidylcholine (0.56 g), sodium taurocholate (0.67 g) and propionic acid (560 μl) in 4 ml of water was prepared and brought to 71 ° C. (solution 2).
Micro 1 is then poured into solution 2 to obtain a clear microemulsion at 71 ° C., after which it is dispersed under stirring in 8 times the volume of water at 1 ° C. with respect to the volume of the microemulsion. 46 ml of lipid nanospheres were obtained.
Finally, the dispersion was washed three times by tangential flow filtration using a VIVAFLOW50 100 kDa cut-off, adding 46 ml of water each time.
The nanospheres had an average diameter of 141 nm and a polydispersity index of 0.36 as measured with a Malvern Zetasizer 3000HS.

Example 3
0.36 g of stearic acid, 0.36 g of palmitic acid and 0.28 g of soybean phosphatidylcholine were melted at about 52 ° C. Then 400 μl isopropyl alcohol and 0.12 g sodium taurocholate were added. Then 400 μl of a solution of the compound of formula II (9 mg / ml) in 0.05 mM H ₂ SO ₄ aqueous solution was added to give a clear microemulsion (Micro 1).
Separately, a solution of soybean phosphatidylcholine (0.35 g), sodium taurocholate (1.2 g), isopropyl alcohol (800 μl) and 0.05 ml of 0.05 mM H ₂ SO ₄ aqueous solution was prepared and brought to 52 ° C. (solution 2).
Micro 1 is then poured into solution 2 to obtain a clear microemulsion at 52 ° C., which is then dispersed under stirring in 10 times the volume of water at 1 ° C. with respect to the volume of the microemulsion. 96 ml of lipid nanospheres were obtained.
Finally, the dispersion was washed twice by tangential flow filtration using a PALL MINIMATE TFF capsule 100 kDa cut-off, adding 96 ml of 0.032 mM HCl aqueous solution each time.
After adding dextran (3 g with respect to 100 ml of dispersion), the dispersion was lyophilized.
The nanospheres obtained after the lyophilization process had an average diameter of 324 nm and a polydispersity index of 0.5 as measured with a Malvern Zetasizer 3000HSA.

Example 4
0.4 g of stearic acid and 0.28 g of soy phosphatidylcholine were melted at about 72 ° C. Then 200 μl of isopropyl alcohol and 0.06 g of sodium taurocholate were added. Then 200 μl of the compound of formula II (9 mg / ml) in 10 mM HNO ₃ aqueous solution was added to obtain a transparent microemulsion (micro 1).
Separately, a solution of soybean phosphatidylcholine (0.35 g), sodium taurocholate (0.67 g) and isopropyl alcohol (400 μl) in 4 ml of 10 mM HNO ₃ aqueous solution was prepared and brought to 72 ° C. (solution 2).
Micro 1 is then poured into solution 2 to obtain a clear microemulsion at 72 ° C., which is then dispersed under stirring in 6 times the volume of water at 1 ° C. with respect to the volume of the microemulsion. 32 ml of lipid nanospheres were obtained.
Finally, the dispersion was washed twice by tangential flow filtration with the addition of 32 ml HNO ₃ (1 mM) aqueous solution each time using a VIVAFLOW50 100 kDa cutoff.
The nanospheres had an average diameter of 140 nm as measured with a Malvern Zetasizer 3000HSA and the polydispersity index was 0.26.

Example 5
0.4 g of stearic acid and 0.32 g of soy phosphatidylcholine were melted at about 70 ° C. Then 280 μl of octanoic acid and 0.04 g of sodium taurocholate were added. Then 200 μl of the compound of formula II (9 mg / ml) in 0.01 N HCl aqueous solution was added to obtain a clear microemulsion (Micro 1).
Separately, a solution of soy phosphatidylcholine (0.32 g), sodium taurocholate (0.66 g), octanoic acid (40 μl) and isopropyl alcohol (400 μl) and water 4 ml was prepared and brought to 70 ° C. (solution 2).
Micro 1 is then poured into solution 2 to obtain a transparent microemulsion at 70 ° C., after which it is dispersed with stirring in 8 times the volume of water at 1 ° C. relative to the volume of the microemulsion. 44 ml of lipid nanospheres were obtained.
Finally, the dispersion was washed twice by adding 44 ml of water each time and ultrafiltration with a 100 kDa cutoff.
The nanospheres had an average diameter of 242 nm and a polydispersity index of 0.20 as measured with a Malvern Zetasizer 3000HSA.

Claims (6)

  Solid lipid nanoparticles of platinum compounds.   The solid lipid nanoparticle according to claim 1, wherein the platinum compound is a platinum complex. The platinum complex has the formula I:

Trans- {bis [trans (diamine) (chloro) platinum (II) (μ-1,6-hexanediamine)]} diamine platinum tetranitrate,
Formula II:

Bis {trans (diamine) (chloro) platinum (II)} μ- (1,16-diamino-7,10-diazahexadecane-N ¹ , N ¹⁶ ) dinitrate. 2HNO ₃ ,
Formula III:

Bis {trans (diamine) (chloro) platinum (II)} μ- (1,16-diamino-6,11-diazahexadecane-N ¹ , N ¹⁶ ) dinitrate. 2HNO ₃ ,
Formula IV:

Bis {trans (diamine) (chloro) platinum (II)}-μ- (1,12-diamino-4,9-diazadodecane-N ¹ , N ¹² ) dinitrate. 2HNO ₃ ,
Formula V:

Bis {trans (diamine) (chloro) platinum (II)}-μ- (1,8-diamino-4-azaoctane-N ¹ , N ⁸ ) dinitrate. Solid lipid nanoparticles according to claim 2, wherein the solid lipid nanoparticles are selected from HNO ₃ . A method for producing solid lipid nanoparticles according to any one of claims 1 to 3,
a) preparing a first microemulsion by mixing molten lipid, surfactant and optionally a co-surfactant, and an aqueous platinum compound;
b) mixing the surfactant and optionally the co-surfactant in water, preferably heating to the complete solution at the same melting temperature as the lipid used in a) and adding the co-surfactant, Preparing a solution;
c) The microemulsion obtained in a) is dispersed in the solution obtained in b) to obtain a multiple microemulsion c);
d) The microemulsion obtained in c) is dispersed in an aqueous medium at a temperature in the range of 0.5-4 ° C. to obtain solid lipid microspheres;
e) The lipid microspheres obtained in d) are washed with an aqueous medium through ultrafiltration and lyophilized, optionally in the presence of a swelling agent and a cryoprotectant;
A method involving that.   The pharmaceutical composition containing the solid lipid nanoparticle of any one of Claims 1-3.   A method for treating a patient affected by a cancer sensitive to a platinum complex, the method comprising administering to the patient a therapeutically effective amount of the solid lipid nanoparticles of any one of claims 1-3.